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Venetoclax and Selinexor in Treating Patients with Relapsed or Refractory High Risk Hematologic Malignancies

This phase Ib trial studies the side effects and best dose of venetoclax and selinexor and how well they work in treating patients with high risk hematologic malignancies such as diffuse large B-cell lymphoma, multiple myeloma, or acute myeloid leukemia that have come back (recurrent) or do not respond to treatment (refractory). Venetoclax functions by inhibiting or slowing down a protein in the body called bcl-2, which is involved in slowing down the normal process by which old cells in the body are cleared (called apoptosis). Selinexor functions by trapping “tumor suppressing proteins” within the cell and causing the cancer cells to die or stop growing. This study examines the effects, if any, of selinexor and venetoclax on high risk hematologic malignancies and on the body, including any side-effects.
Hematologic, Leukemia, Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome, Phase I
Phase I
Chemotherapy - cytotoxic, Mol. targeted/Immunotherapy/Biologics
Selinexor (KPT-330), Venetoclax
Byrne, Michael
Roswell Park Cancer Institute, UT Southwestern Medical Center, University Hospitals of Cleveland, Vanderbilt University


18 Years
Inclusion Criteria:

Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure

Life expectancy > 12 weeks

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Histologically confirmed diagnosis of one of the following, in accordance with World Health Organization (WHO) diagnostic criteria: * Escalation: ** Diffuse large B-cell lymphoma (DLBCL, including primary mediastinal large B cell lymphoma, T cell rich B cell lymphoma, and high-grade B cell lymphoma not otherwise specified [NOS]). Patients with Burkitt’s, lymphoblastic lymphoma, follicular lymphoma, and mantle cell lymphoma are not included OR ** Acute myeloid leukemia (AML) * Expansion: ** DLBCL and AML as above. ** Venetoclax (VEN) refractory expansion cohort (DLBCL or AML only): Patients must have previously received and failed venetoclax therapy (either monotherapy or combination) during their treatment course (i.e., patients may receive non-VEN therapy immediately prior to enrollment on this study). Treatment failure is defined as evidence of disease progression after >= 1 cycle (four weeks) of full-intensity venetoclax-based therapy (i.e., 28 days exclusive of ramp-up. Patients that require dose reductions due to intolerance may be considered for this cohort after discussion with the sponsor.)

Relapsed or refractory following >= 1 line(s) of prior therapy

Patients that relapse >= 3 months after allogeneic hematopoietic cell transplantation (HCT) are eligible

Female patients of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at screening. Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment

For leukemia and DLBCL with known or suspected marrow involvement, patients must have at least 2-3 mL of bone marrow aspirate material obtained within 14 days of beginning treatment on this study. Patients with DLBCL must have 3-5 unstained slides, or tissue block, available for evaluation within 14 days of study enrollment in the expansion cohorts. DLBCL patients enrolled during the escalation phase must have blocks available for submission within 28 days of beginning treatment

DLBCL: Hemoglobin (Hgb) >= 10 g/dL

DLBCL: Platelets >= 75,000 cells/mm^3

DLBCL: Absolute neutrophil count (ANC) >= 1,000 cells/mm^3

Total bilirubin
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to
Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula)

Patients with laboratory evidence of liver or kidney dysfunction secondary to underlying disease, that is expected to reverse with treatment, may be enrolled after discussion with the sponsor/investigator

Exclusion Criteria:

Patients who are pregnant or lactating

Patients who received any systemic anticancer therapy including investigational agents or radiation =
Inadequate recovery from toxicity attributed to prior anti-cancer therapy. With the exception of alopecia or fatigue, patients must have recovered to baseline or =
Participation in another clinical trial with any investigational drug within 14 days prior to study enrollment

Patients included in the VEN refractory cohort that have discontinued venetoclax therapy (either monotherapy or combination) due to toxicity or hypersensitivity, including prior history of grade 3/4 tumor lysis syndrome (TLS) during prior VEN exposure

In dose expansion cohorts, except venetoclax relapsed cohort, no prior treatment with selective inhibitor of nuclear export (SINE) compounds, another XPO1 inhibitor, or BCL-2 inhibitors

Active graft versus host disease (GVHD) requiring calcineurin inhibitors or steroid dosing >= 10 mg/day prednisone (or equivalent) or
Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral

Major surgery within 2 weeks of first dose of study drug

Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator’s opinion, could compromise the patient’s safety

Unstable cardiovascular function: * Symptomatic ischemia, or * Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia therapy are excluded; 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block (LAFB)/right bundle branch block (RBBB) will not be excluded), or * Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or * Myocardial infarction (MI) within 3 months

Known active hepatitis B or hepatitis C infection (hepatitis testing is not required as part of this study)

Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study)

Subject has received the following =
Subject has received the following =
Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit =
Inability to swallow oral medication; or the presence of a poorly controlled gastrointestinal disease, disorder, syndrome, or dysfunction that could significantly affect the absorption of oral study drug – e.g. Crohn’s disease, ulcerative colitis, chronic diarrhea (defined as > 4 loose stools per day), malabsorption syndrome, or bowel obstruction

Inability or unwillingness to take required and recommended medications intended to prevent and treat potential adverse events of tumor lysis syndrome (TLS), nausea and vomiting, loss of appetite, and fatigue

Patients unwilling to comply with the protocol

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